This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this project, we will test the value of [18F]EF5-PET imaging to detect reduction in tumor hypoxia, using two novel approaches, alone or in combination. Both approaches are based on the exclusive requirement of glucose as an energy source for hypoxic cells. We previously reported that inhibition of the transcription factor, HIF-1, blocks the synthesis of glycolytic enzymes, thereby preventing hypoxic tumor cells from using glucose. Chronic HIF-1 inhibition led to hypoxic cell necrosis. The second approach that we have recently discovered is based on the fact that solid tumors contain a mixture of oxygenated and hypoxic regions. Hypoxic tumor cells primarily use glucose for energy production by glycolysis and release lactate. In the presence of oxygen, certain tumors are able to import lactate via the monocarboxylate transporter MCT1, and oxidize it to recover ATP. In this setting, lactate is a preferred substrate to glucose in the respiration process. Inhibition of MCT1 delays tumor growth and increases their sensitivity for radiotherapy due to the switch-over of oxidative tumor cells from lactate oxidation to glucose catabolism. This switch leads to death of hypoxic cells from glucose starvation. In this study we will monitor the efficiency of selective hypoxic cell kill in solid tumors upon inhibition of lactate transport (MCT1) and HIF-1[unreadable], using the hypoxia imaging agent [18F]EF5 as a quantitative PET tracer of hypoxia. We will compare the [18F]EF5 PET signal with the immunohistochemical analysis of EF5 binding. The goal of this project is to establish the potential of PET imaging technique, in combination with hypoxia imaging agent [18F]EF5, to monitor the success of hypoxia cell kill therapy in a non invasive manner.